According to this recent Quartz article:

The theory that [depression is] caused by chemical imbalances is false.


[Chemical imbalance as the cause of depression] was once a tentatively-posed hypothesis in the sciences, but no evidence for it has been found, and so it has been discarded by physicians and researchers. Yet the idea of chemical imbalances has remained stubbornly embedded in the public understanding of depression.

The article seems well-researched but I did not see any primary references going directly to this central claim that the "chemical imbalance" hypothesis has been displaced, only that there's great variance in response to various drugs.

Is "The theory that [depression is] caused by chemical imbalances is false." an accurate statement?

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    Commented Jan 9, 2018 at 22:13

2 Answers 2


Yes and no. Usually the "chemical imbalance" is the consumer-oriented version of the serotonin hypothesis for depression. The most practiced method of testing this experimentally (and practically the only one available for live humans) is acute tryptophan depletion (ATD); tryptophan is a precursor for serotonin. It's been experimentally verified via PET scanning (with the appropriate tracer) that ATD does lower serotonin in everyone, although it does so more in women than in men.

So does lower serotonin (via ATD) cause depression?

  • Yes, in some previously depressed individuals (actually in about half of them), experimentally lowering serotonin via ATD causes a rebounce in depression. See e.g. Booji et al.

  • and no, in healthy individuals lowering serotonin via ATD doesn't seem to cause depression. Mood changes in healthy men are particularly hard to detect at all following ATD, while some minor mood changes have been reported in women; see Ellenbogen et al..

One review (Young, 2013) says

As mentioned, the ATD technique was originally developed to see whether the association between low serotonin and low mood was causal. The older results suggesting an association between low serotonin and low mood support the idea that when ATD lowers mood it does so by decreasing release and function of serotonin. However, the effect of ATD on mood depends on the characteristics of the individuals being studied, with effects ranging from nothing, to a dramatic lowering of mood in newly discovered depressed patients who are treated with serotonergic antidepressants.

Another review by Jenkins et al. (2016) says:

Tryptophan depletion studies in never-depressed individuals are variable, with no or little overall effect on lowering of mood [45,46]. Interestingly, reports of moderate mood lowering are seen more often in studies with healthy women than in studies with healthy men [47]. However in never-depressed healthy volunteers who are at high risk for depression through a familial risk factor, acute tryptophan depletion produces clear abnormalities in mood control [48,49]. Finally, in remitted depressed patients, temporarily lowering tryptophan levels can result in an acute depressive relapse [50,51,52] with transient exacerbation of symptoms associated with patients taking serotonergic anti-depressants [53,54]. These studies reveal that subjects with a pre-existing vulnerability in the serotonergic system may be most susceptible to a tryptophan challenge. Moreover, low serotonin can indeed contribute to a lowered mood state, however this cannot occur in isolation—it must be in concert with some other unknown system (perhaps neurotransmitter or genetic) that interacts with the reduced serotonin to decrease mood.

So it depends how you interpret the statement "The theory that [depression is] caused by chemical imbalances is false." If you interpret it as "serotonin depletion doesn't cause depression in anyone", that's obviously false. If you interpret it as "serotonin depletion doesn't cause depression in everyone", then it may be true. Not all limitations of ATD are understood though; see Young's review for details.

Likewise there is a (less often discussed in the press) catecholamine hypothesis of depression. And the result of simulating it via a similar method to ATD, namely acute phenylalanine/tyrosine depletion (APTD) or via a dissimilar method, namely blockade of catecholamine synthesis by administration of alpha-methyl-para-tyrosine (AMPT)... produce similarly confusing results:

Mood responses to AMPT depletion in healthy subjects are usually not significant. The presence of depressive symptoms induced by catecholamine depletion in unmedicated remitted patients with MDD suggests state independence of this biological marker. The depressive symptoms evoked by catecholamine depletion are often similar to those experienced by patients during a depressive episode, suggesting clinical plausibility. However, catecholamine depletion failed to exacerbate depression in untreated, symptomatic depressed patients prior to initiation of antidepressant therapy. This finding may be due to brain catecholamine function being maximally dysfunctional in symptomatic depressed patients (a ceiling effect). Catecholamine depletion reversed the therapeutic effects of antidepressants in treated depressed patients, particularly the effects of catecholamine reuptake inhibitors. Catecholamine depletion also reversed the effects of light therapy in patients with seasonal affective disorder.


In healthy individuals, APTD (like AMPT) does not induce depressive symptoms. [...] Finally, in a study of euthymic subjects with a history of major depression, APTD attenuated DA [dopamine] function, reflected by increased plasma prolactin levels, and decreased spatial memory performance.However, ratings of depression were unaffected, suggesting that disruption of dopaminergic function by APTD (unlike disruption of serotonergic function by tryptophan depletion) does not induce a lowering of mood in individuals who are vulnerable to depression.

And the overall opinion of this review-ish book chapter by Kumar et al. (2013) (which also covered ATD studies) was that

the current prevalent view is that the monoamine hypothesis may only partially explain MDD [major depressive disorder] and the response to antidepressant drugs.

And since the latest and greatest anti-depressant is ketamine and its derivatives (some of which have been fast-tracked by the FDA as breakthrough drugs; see Time's feature for instance), there's the obligatory glutamate hypothesis of depression based on the ketamine's mechanism of action; see Sanacora et al.(2011). I'm not aware of experimental protocols like ATD for lowering glutamate (in humans) to see what happens though; animal models have had somewhat mixed results according to the previously mentioned paper.

Perhaps an interesting twist to this latter theory is that some recent research found glutamate co-signaling in some serotonergic pathways. A fairly recent theory proposal by Fischer et al. (2014) tries to use this to explain the "delayed onset of action" of monoamine-based antidepressants. (I personally find the "delayed onset of action" terminology misleading because what happens in responders is a slow cumulative effect.) I'm not aware of any experimental ways in which this dual-signaling theory was tested in humans.


This is not even wrong. Depression is related to alterations of serotonin, dopamine transmitters and more:

On the Complexity of Brain Disorders: A Symptom-Based Approach:
Major Depressive Disorder (MDD) is a psychiatric disorder characterized by reduced mood, anhedonia, psychomotor retardation, and learned helplessness, among others (Kennedy, 2008). It is known that MDD involves changes to different neurotransmitters, while the most salient change is to serotonin. There are also changes to dopaminergic and noradrenergic transmission (Nutt, 2008). MDD is also associated with changes to brain volumes and connectivity networks among different brain regions. For example, studies have reported reduced gray matter volume in the anterior cingulate (van Tol et al., 2010) and hippocampus (Videbech and Ravnkilde, 2004) in patients with MDD. Other studies reported increased connectivity among the anterior cingulate and medial temporal lobe (de Kwaasteniet et al., 2013), while others reported a decrease in the functional connectivity in the insula and amygdala (Veer et al., 2010). These findings highlight the fact that MDD is associated with multiple neural dysfunctions. These previously mentioned studies did not, however, map these neural abnormalities to specific symptoms in depression. However, there are some studies that have attempted to understand the neural correlates for each symptom in depression (Vrieze et al., 2014). For example, Argyropoulos and Nutt (2013) found that anhedonia (the inability to experience pleasure) is related to dopamine reduction, while reduced mood is related to decreased serotonin levels. Some studies have investigated the neural substrates of psychomotor retardation (lack of energy and reduced movement) in depression, and suggested that reduced dopamine is also implicated (Liberg and Rahm, 2015). It is possible that reduced dopamine levels in the ventral striatum is related to anhedonia whereas reduced dopamine levels in the dorsal striatum is related to psychomotor retardation (Stein, 2008). In addition, it was suggested that reduced mood and sadness in MDD is associated with dysfunction in the prefrontal cortex, particularly, the orbitofrontal cortex (Drevets, 1999; Mayberg et al., 1999; Davidson et al., 2002; Drevets et al., 2002; Lévesque et al., 2003). Although the studies mentioned above have mapped certain symptoms of MDD to separable neural dysfunctions, the exact mechanism of these observations remains unclear.

So the neurotransmitters are the 'chemicals' and if they deviate from 'normal' levels, concentrations etc., they are in 'imbalance'? And this then causes depression. That is a very unfortunate leap from a probabilistic correlation to a simple mechanistic causation hypothesis. Even "separable neural dysfunctions" are a very far cry from understanding just a subset of symptoms, let alone "depression".

It is unproven what comes first, the imbalance or the depression. It is unproven that achieving a 'desirable balance' cures depression:

The emperor's new drugs: medication and placebo in the treatment of depression:
Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by the drug companies reveal that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close to any theory in the history of science having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future.

So why is this theory still so popular? Just because a chemical imbalance can be chemically balanced? With marketable drugs, of course?

Medical models and metaphors for depression:
The aetiology of depression is not fully understood, which allows many different perspectives on aetiology to be adopted. Researchers and clinicians may be attracted to concepts of aetiology that parallel other diagnoses with which they are familiar. Such parallels may assume the role of informal models or metaphors for depressive disorders. They may even function as informal scientific theories of aetiology, energising research activities by guiding hypothesis generation and organising new knowledge. Parallels between different types of disease may ultimately prove valuable as frameworks supporting the emergence and maturation of new knowledge. However, such models may be counterproductive if their basis, which is likely to lay at least partially in analogy, is unacknowledged or overlooked. This could cause such models to appear more compelling than they really are. Listing examples of situations in which models of depression may arise from, or be strengthened by, parallels to other familiar conditions may increase the accessibility of such models either to criticism or support.
Depression as a chemical imbalance
Many diseases are viewed as imbalances in allostatic or homeostatic physiological processes. Normal physiology includes countless examples of tightly regulated feedback loops and self-limiting processes. A good example is the regulation of thyroid and other endocrine hormones. A perturbation of regulatory mechanisms (e.g., due to a thyroid tumour that has escaped suppression or a thyroid gland unable to produce sufficient hormone despite maximal stimulation) leads to physiological imbalances that produce disease states (Larsen, 1982). Another example is Parkinson’s disease, where motor symptoms are attributed to a dopamine–acetylcholine imbalance resulting from reduced striatal dopaminergic tone and subsequent cholinergic overactivity (Calabresi et al. 2006). This general idea of an imbalance between physiological processes that are normally (in health) tightly regulated may contribute to the popularity of the common metaphor of a ‘chemical imbalance’. This particular metaphor has been criticised as representing something more akin to a cultural narrative than a theoretical driver of scientific thinking in psychiatry (France et al. 2007). It may be used by clinicians who feel that it reduces stigma (perhaps by diminishing any implication of moral responsibility for depression), although available evidence suggests that such explanations may actually be associated with increased stigma (Speerforck et al. 2014).[…]
Because scientific theories are clearly articulated and lead to testable assumptions, they play an important role in the advancement of research, and ultimately in clinical and public health practices. Well established disease models may also assist clinicians with the selection and personalisation of treatment. Pathophysiological models can also effectively guide research.
However, good theories and models depend on an advanced state of knowledge that has thus far eluded the sciences underlying much of psychiatric practice.
When they are not clearly articulated, theoretical ideas and models may nevertheless retain their influence. As the examples listed above may serve to illustrate, there are several ideas, empowered by parallels to other clinical conditions in medicine that may act as informal theories guiding psychiatric research and practice in particular directions. Their ability to impact on the emerging understanding of depression may unfold at many levels such as: the popular depiction of these disorders in media, the prioritisation of research funding and the selection of papers for publication through peer review processes. It is important to recognise that some of this influence may arise by analogy with other diseases. These ideas may take on greater intellectual weight because of their ‘pedigrees’ in the history of medicine rather than through their actual scientific promise or the weight of scientific evidence behind them.

This gave an overview of eight currently competing models, chemical imbalance quote singled out here. Taking some hints on how scientific theories originate, operate and outlast others might be useful. Well, if 'chemical imbalance' indeed is able to do so:

The "Chemical Imbalance" Explanation for Depression: Origins, Lay Endorsement, and Clinical Implications:
Modern chemical imbalance hypotheses of depression originated in the mid-20th century, spurred by important discoveries such as the efficacy of chlorpromazine for psychosis; findings that monoamines exist within the central nervous system (CNS) and act as neurotransmitters; and an early understanding of monoamine synthesis, storage, release, and deactivation. Such discoveries also quickened the emergence of psychopharmacology as a discipline and helped lead to the eventual widespread practice of using prescription drugs to treat mental disorders also (e.g., Healy, 2001). […]
Also interfering with response-equals-causation logic are findings that in many clinical trials, antidepressants have exhibited either no or very modest advantages in comparison with placebos (Kirsch, Moore, Scoboria, & Nicholls, 2002; Kirsch, Scoboria, & Moore, 2002).
So Where Do We Stand Today?
In sum, the pathophysiology of depression remains poorly understood (Hindmarch, 2001; Hirschfeld, 2000), and a simplistic chemical imbalance explanation for depression likely lacks ade- quate validity (Hindmarch, 2002). Monoamine deficiencies continue to be mentioned by some researchers as a potential cause of depression (e.g., Bianchi et al., 2002), but others have declared simply that the monoamine hypothesis “is incorrect” (Owens, 2004, p. 6). Researchers have increasingly turned toward investigations of other potential biological causes of depression (e.g., Hindmarch, 2001; Leonard, 2000; McEwen, 1999). Related efforts to identify distinct brain changes before, during, and after depression treatment are also ongoing (e.g., Cook et al., 2005; Sheline, 2003).

However, there are currently no widely available anatomical, chemical, or other biological tests that reliably distinguish the brains of depressed persons from nondepressed persons (e.g., Antonuccio et al., 1999). Multiple etiological models (including biological, environmental, and interactional) of depression remain viable at present.
The Chemical Imbalance Explanation as Cultural Narrative Despite its flaws, the chemical imbalance explanation remains the potentially dominant cultural story of depression etiology in the United States (e.g., Smith, 1999). However, cultural narratives of mental illness do not necessarily reflect an objective reality or universal understanding. Different historical and cultural traditions frame depressive experiences within different contexts, thereby promoting and/or limiting particular symptoms and shaping different understandings and meanings of depression and its appro- priate treatment. Such narratives are probably best conceptualized as social constructions that must be understood within the cultural context that socializes, interprets, and responds to them (Marsella & Kaplan, 2002). […]
Currently, depression is not diagnosed via objective chemical tests, nor is treatment guided by any such tests. If depression did result primarily from a known chemical imbalance, such tests would likely be available and in widespread use, and depression would be easily and quickly resolved for most patients.


Is "The theory that [depression is] caused by chemical imbalances is false." an accurate statement?

Yes. At best this theory is an oversimplification. More accurate now, it seems the outlook is that a once promising hypothesis has failed to provide a convincing explanation for the causes nor the 'cures', has failed to accurately predict the outcomes of medications and other interventions, and plainly way too often does not work as advertised, but sells very well.

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